BG60316B2 - ACETAMIDE PRODUCTS - Google Patents

Abstract

Novel n-phenylacetyl and related acyl derivatives of /4-amino-2,6-dimethylphenylsulfonyl/nitromethane and their pharmaceutically acceptable salts are inhibitors of the enzyme aldose reductase and can be used to treat certain side effects of diabetes and galactosemia. Also presented are pharmaceutical compositions containing one of the derivatives, as well as methods for obtaining and using the derivatives. 11 claims

Description

The invention relates to novel phenylacetamide derivatives which are inhibitors of the enzymatic aldose reductase and which are of importance, for example in the treatment of certain side / peripheral effects in diabetes or galactosemia. The invention also relates to a method for treating one or more of these side effects using an acetamide derivative and to pharmaceutical compositions containing the acetamide derivative. In addition, the invention relates to novel methods for the preparation of new derivatives and for the preparation of medicaments containing any of said derivatives.

The enzymatic aldose reductase causes the catalytic conversion of aldoses, such as glucose and galactose, into the corresponding alditols, respectively in sorbitol and galactite (ol), in warm-blooded animals and in humans. Alditols pass through cell membranes difficult and, once formed, can only be removed by further metabolism. Therefore, alditols tend to accumulate inside the cells where they form, causing an increase in internal osmotic pressure, which in turn may be high enough to disrupt or disrupt the cells themselves. In addition, elevated aldithol levels can lead to unnatural levels of their metabolites, in which they themselves can impair or disrupt cellular function. Enzyme aldose reductase has relatively low substrate affinity and is usually effective only in the presence of relatively high concentrations of aldose. Such high concentrations exist in the clinical setting of diabetes (excess glucose) and galactosemia (excess galactose). Therefore, aldose reductase inhibitors are useful in reducing or preventing the development of those side effects of diabetes or galactosemia, which may be due in part to the accumulation of sorbitol or galactite in the eye, nerve or kidney tissues, respectively. Such side disorders include, for example, macular edema, cataracts, retinal disease, nerve disease, and impaired nerve conduction.

Although a number of aldose reductase inhibitors have been identified and clinically evaluated, there is a continuing need for alternative inhibitors. A series of (phenylsulfonyl) nitromethane derivatives as inhibitors of the enzymatic aldose reductase is described in (1). It is now discovered that a specific group of novel phenylacetamide derivatives, referred to below, are effective inhibitors of aldose reductase, which is the basis of the present invention.

According to the invention there is provided a new phenylacetyl derivative of the compound (4-amine-2,6-dimethylphenylsulfonyl) nitromethane of formula I (hereinafter referred to together with other chemical formulas denoted by Roman numerals), wherein R® and R * are each hydrogen. , (1-4C) alkyl, (1-4C) alkoxy, cyano or trifluoromethyl, or together form (2-6) alkylene, or R * together with R ² from the adjacent benzene ring A forms metallic, ethylene, oxyethylene, ethyleneoxy, methylenoxymethylene, vinyl, trimethylene or tetramethylene; and in the benzene ring A, one, two or three of the substituents R ² , R ³ , R ⁴ , R ^J and R * are each independently selected from hydrogen, halogen, trifluoromethyl, nitro, cyano, (1-4C) alkyl and / 1- 4C / alkoxy, and the other substituents R ² - R ⁶ are hydrogen; or a suitable pair of situated R ² , R ³ , R ⁴ , R ⁵ and R ⁶ forms (together with the adjacent carbon atoms) another benzene ring, wherein it itself may be optionally substituted by halogen, (1-4C) alkyl or (1-4C) alkoxy substituent, another of the substituents R ² - R ⁴ is hydrogen, halogen, trifluoromethyl, nitro, cyano, (1-4C) alkyl or (1-4C) alkoxy, and the remaining R ² - R * are hydrogen; or a pharmaceutically acceptable salt thereof.

Depending on the nature of the substituents (for example, the meanings of R® and R ¹ ), the compounds of formula I may contain one or more chiral centers and may exist and be isolated in one or more racemic and enantiomeric forms. It should be clear that the present invention encompasses any of these forms which has a beneficial effect as an enzyme aldose reductase inhibitor, while it is well known to those skilled in the art how to obtain individual enantiomers (e.g., by synthesis of chiral intermediates or by separating the racemic forms, for example by chromatography on a chiral basis, and how to evaluate their efficacy as aldose reductase inhibitors (e.g., by the test procedure described below).

It should be clear that in the present specification, general terms such as "alkyl" include all isomeric possibilities, i.e. both normal (straight) and branched forms. However, the names of the individual radicals, such as "propyl", are specific to the form indicated, i.e. the shape of the normal chain, with each branch branch being specified.

A particular value of R® and R ^1, where / 1-4C / alkoxy, for example methoxy, ethoxy or isopropoxy, of which methoxy is of particular interest.

Specific combinations of R® and R ¹ of interest include, for example:

/ a / R® = R ¹ = hydrogen; / b / R® - hydrogen and R ¹ - methyl; (c) R (R ⁾ = hydrogen and R ¹ - ethyl; (d) R (R ^{) is} hydrogen or methyl and R ¹ = cyan; (d) R (R) is hydrogen or trifluoromethyl and R ^{1 is} methoxy or ethoxy and (e) R is R and R ¹ together = ethylene.

A particular value for R® and R ¹ when together they constitute / 2-6C / alkylene is, for example, ethylene, 1,1-dimethylethylene, trimethylene, tetramethylene or pentamethylene.

Specific values for common substituents as described above in the benzene ring include, for example: for halogen fluorine, chlorine, bromine; for (1-4C) alkyl-methyl, ethyl, propyl, isopropyl and isobutyl and for (1-4C) alkoxy-methoxy and ethoxy.

A specific value for an optional substituent that may be present in the second benzene ring when a pair of R ² R ⁶ , as described above, forms such a ring is, for example, fluorine, chlorine, methyl or methoxy.

One specific group of compounds within the invention includes two- or three-ring amides of formula Ia, below, wherein Q is methylene, ethylene, oxyethylene, ethyleneoxy, vinylene, or trimethylene and the substituents R ³ - R ⁶ in the benzene ring A having any of the foregoing meanings, and pharmaceutically acceptable salts thereof.

A preferred group of compounds of the invention include compounds of formula II described below, wherein Ra and Rb are each hydrogen, methyl, ethyl or cyano, or one of Ra and Rb is hydrogen or trifluoromethyl and the other is methoxy, ethoxy or isopropoxy ; and the benzene ring B is selected from phenyl,

2-halogenphenyl (in particular 2-fluoro or 2-chlorophenyl), 2- (1-4C) alkylphenyl (in particular 2-methylphenyl), 2- (1-4C) alkoxyphenyl (in particular 2-methoxyphenyl), 4- (1-4C) alkoxyphenyl (especially 4-methoxy or 4-ethoxyphenyl) and 2,4,6-tri (1-4C) alkyl / phenyl (in particular 2,4,6-trimethylphenyl); and pharmaceutically acceptable salts thereof.

Another group of compounds of particular interest consists of compounds of formula IIa, described below, wherein the acyl is selected from: phenylacetyl, (2,4,6-trimethylphenyl) acetyl, (2-methylphenyl) acetyl, /

2-fluorophenyl / acetyl, (2-chlorophenyl) acetyl, (2-methoxyphenyl) acetyl, 1- (4-chlorophenyl) -1-cyclopropanecarbonyl, 1- (phenyl) -1-cyclopropanecarbonyl, (4-ethoxyphenyl) acetyl, / R, S (-2- (phenyl) propionyl, (4-methoxyphenyl) acetyl, N, S) -benzocyclobutanecarbonyl, (2-bromophenyl) acetyl, (2-nitrophenyl) acetyl,

2- (4-chlorophenyl) -2-methylpropionyl, (4-methoxy-3-methylphenyl) acetyl, (3-fluorophenyl) acetyl, N, 8 / -2-methoxy-2- (2-fluorophenyl) acetyl, (2) -trifluoromethylphenyl / acetyl, (3,4difluorophenyl) acetyl, (2,6-dichlorophenyl) acetyl, (4-trifluoromethylphenyl) acetyl, (4-chlorophenyl) acetyl, (3-methylphenyl) acetyl, (3-methoxyphenyl) acetyl, acetyl) -phenylcyclopentanecarbonyl, 1- (4-methoxyphenyl) cyclopropanecarbonyl, (2-naphthyl) acetyl, (RS) -1- (4chlorophenyl) cyclobutanecarbonyl, (1-naphthyl) acetyl, (2-methyl-6-nitrophenyl) acetyl, acetyl) acetyl (acetyl,) 3,4-dichlorophenyl) acetyl, (2,4-dichlorophenyl) acetyl, (RS) -2- (4-isobutylphenyl) propion yl, N-3,3,3-trifluoro-2-methoxy-2-phenylpropionyl, (S) -3,3,3-trifluoro-2-methoxy-2-phenylpropionyl, (R, S) -2-methoxy-2 - (2-methylphenyl) acetyl, (S) -2-methoxy-2-phenylacetyl, (R, S) -1,2,3,4-tetrahydro-1-naphthoyl, (R) -2-methoxy-2-phenylacetyl, N, 5 / -2-methoxy-2-phenylacetyl, (R, S) -2- (2-chlorophenyl) -2-methoxyacetyl, (R, S) -2 (2-chlorophenyl) -2-isopropoxyacetyl,

3-indenylcarbonyl, (R, 5) -1-indenylcarbonyl, (N, 5) -2- (3-fluoro-2-methylphenyl) -2-methoxyacetyl, (R, S) -2- (2,6-difluorophenyl) (-2-methoxyacetyl, (2,6-difluorophenyl) acetyl, (1-isochromanyl) carbonyl, /% 5) -2-cyano-2- (phenyl) propionyl, (RS) -2-methoxy-2- (2-methoxyphenyl) (acetyl, N, 5 / -2- (2,3-difluorophenyl) -2-methoxyacetyl, (S) -2-phenylpropionyl, (R) -2-phenylpropionyl, (N, 5) -2- (2- methylphenyl / propionyl, (R, S) -2-phenylbutyryl, (RS) -2-ethoxy-2- (phenyl) acetyl and (R, S) -2-ethoxy-2 (2-methylphenyl) acetyl; and pharmaceutically acceptable salts thereof.

Another group of compounds of the present invention includes compounds of formula IIa wherein the acyl is selected from: (R) -

2-methoxy-2- (2-methylphenyl) acetyl, (RS) -2ethoxy-2- (2-fluorophenyl) acetyl, 2- (2,3-dimethylphenyl) acetyl, 2- (2,6-dimethylphenyl) acetyl, N, 5 (-2- (2,6-difluorophenylpropionyl), (5) -2-methoxy-2- (2-methylphenyl) acetyl, 2- (4-methylphenyl) acetyl, 2- (2-fluorophenyl) propionyl, 2- (2) 2,4-dimethylphenyl / acetyl, (R) -1,2,3,4-tetrahydro-1-naphthoyl, (S) -1,2,3,4-tetrahydro-1-naphthoyl, (R) -2-methoxy- 2- (2-methoxyphenyl) acetyl and (S) -2-methoxy-2- (2-methoxyphenyl) acetyl; and their pharmaceutically acceptable salts.

Specific compounds of the invention are set forth in the accompanying examples and are presented together with their pharmaceutically acceptable salts as a further feature of the invention. A group of exemplary compounds of particular interest comprises the compounds described in Examples 1-12, 19, 37-44, 47-48, 50-52, 60-68 and 71-74; or pharmaceutically acceptable salts thereof. Of particular interest are the compounds described in Examples 2, 3, 3740, 52, 58, 60, 62, 71 and 73 or their pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts include, for example, an alkali metal (such as potassium or sodium), an alkaline earth metal (such as calcium or magnesium), an ammonium and aluminum salt, and organic base salts providing pharmaceutically acceptable cations such as salts with methylamine, dimethylamine, trimethylamine, piperidine and trimethylamine. morpholine.

The novel compounds of the invention can be prepared by standard organic chemistry techniques that are known in the preparation of structurally similar compounds, for example, as described in (1). Such procedures are provided as a further feature of the present invention and are illustrated by the following procedures in which R ^l, R °, benzene ring A and the optional substituents thereon have any of the meanings defined above.

(a) (4-Amine-2,6-dimethylphenylsulfonyl) nitromethane is acylated by reaction with a carboxylic acid of formula III, or with a reactive acylating agent such as acid halide, azide, anhydride or their mixed anhydride.

When using a free acid of formula III, the process is preferably applied in the presence of a suitable condensing agent, for example, carbodiimide such as 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl / carbodiimide) together with N-hydroxytriazole, such as 1-hydroxybenzotriazole and in a suitable solvent or diluent, for example methylene chloride or dimethylformamide, and at a temperature in the range of -20 to + 35 ° C, preferably at or near room temperature. When 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide is used as a condensing agent, it is more conveniently used as a hydrochloride salt (such as the hydrochloride) and preferably in the presence of a suitable organic base, for example, triethylamine.

The acid of formula III can also be used as an alkali metal salt, for example its lithium, sodium or potassium salt. In these cases, a suitable condensing agent such as carbodiimide is optionally used together with N-hydroxytriazole, as described above. In this case, however, when 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrohalide is used as the condensing agent, no organic feed is required.

A particularly suitable reactive acid derivative of formula III is, for example, the acid halide of said acid, for example an acid halide or bromide (which may be obtained, for example, by reaction of the corresponding acid with an agent such as thionyl chloride or bromide), a mixed anhydride of said acid with / 1 -4C (alkanoic acid) as formic acid / or semi (1-4C) alkylcarbonate, obtained, for example, by reaction of said acid with the corresponding alkanoyl halide or (1-4C) alkyl chloroformate (such as isobutyl chloroformate), or the azide of said acid (which may be obtained by reaction of said acid with diphenylphosphorylase and triethylamine, or of the corresponding hydrazide of said acid by reaction with alkylnitrite, such as t-butyl or amylnitrite in the presence of strong acid). When a reactive acid derivative of formula III is used in the application of method (a), it is appropriate to also present a suitable base such as a metal carbonate, for example potassium, sodium, lithium, calcium, barium or magnesium carbonate (of which the preferred is calcium carbonate) or an organic base such as triethylamine, N-methyl-morpholine, N-methylpiperidine or 4- (dimethylamine / pyridine, the reaction being carried out in a suitable solvent or diluent such as dioxane, N, N-dimethylformamide or methylene chloride and at a temperature in g for example at 0 to 40 ° C and preferably at room temperature or near room temperature. When the optical form of a compound of formula I is required, the acid of formula III or its reactive derivative may more conveniently be used as a single enantiomer.

The starting amino compound, / 4-amine-

2,6-Dimethylphenylsulfonyl / nitromethane can be prepared according to any of the general procedures described in (1) or as illustrated in the accompanying examples. The starting carboxylic acids of formula III are generally well known and in many cases commercially available. Alternatively, they can be prepared according to established procedures for structurally analogous carboxylic acids, as indicated in the examples.

(b) Oxidation of thioether of formula (IV). Suitable oxidizing agents for this reaction include any of those well known in the art for the conversion of thio groups to sulfonyl groups and which are compatible with the presence of acylamine and methyl groups which are also present as substituents in the benzene ring. For example, hydrogen peroxide, organic peracid (such as perbenzoic acid) or lead tetraacetate may be used. Alternatively, an alkali metal periodate (such as sodium metaperiodate), persulfate (such as potassium monopersulfate) or permanganate (such as potassium permanganate), or gaseous oxygen may be used in the presence of a suitable catalyst such as platinum. The oxidation is preferably carried out in a suitable conventional solvent or diluent for such oxidations, for example acetic or propionic acid and at a temperature in the general range, for example from 0 to 80 ° C.

In certain cases, the corresponding sulfoxide derivative of the thioether of formula IV can be formed as an intermediate which can be isolated. The method of the present invention also involves oxidizing such sulfoxide intermediates to give a sulfone of formula I, for example by reaction with an alkali metal permanganate (such as potassium permanganate) in a suitable solvent such as acetic acid and at a temperature in the range of, for example, 20 to 80 ° C.

The starting thioether of formula IV can be obtained by known organic chemistry techniques, for example from the potassium or sodium salt of the corresponding thiophenol of formula V by converting it to the corresponding thioacetic acid of formula VI (or its (1-4C) alkyl ester, such as methyl or ethyl ester) by reaction with chloro or bromoacetic acid (or its (1-4C / alkyl ester)) in the presence of a suitable base. The acid of formula VI (or its (1-4C) alkyl ester) is then reacted with (1-5C) alkyl nitrate and (1-6C) alkali metal alkali, for example propyl nitrate and butyllithium, to give an alkali metal salt of the corresponding 2-nitroacetic acid of formula VII or its (1-4C) alkyl ester. The acids of formula VII are unstable and easily decarboxylate, whereby the acidification of the alkali metal salt of an acid of formula VII permits the isolation of a thioether of formula IV. An acid ester of formula VII can be hydrolyzed, for example, using an aqueous base to give the acid of formula VII and then acidified to give the thioether of formula IV.

The thiophenols of formula V can conveniently be obtained by N-acylation of 4amine-2,6-dimethylbenzothiol, using a procedure analogous to that indicated in (a). The 4-amine-2,6-dimethylbenzothiol itself can be obtained, for example, by reaction of 3,5-dimethylaniline with thiocyanogen (obtained from lead (II) thiocyanate and bromine in methyl acetate) or with copper (II) thiocyanate, at which yields 4-amine-2,6-dimethylphenyl isothiocyanate, the latter being then reduced, for example, with sodium borohydride in ethanol to give the required thiol.

(c) Reaction of an alkali metal salt of 4-14-acylamine-2,6-dimethylbenzenesulfonic acid of formula VIII with nitromethane and iodine in the presence of (1-6C) an alkali metal alcoholate such as potassium t-butylate or sodium methylate .

The reaction is preferably carried out in the presence of a suitable polar solvent, for example, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU) or Ν, ди-dimethylformamide (which are preferred). , or L1-methyl-2-pyrrolidone and at a temperature in the range of, for example, -30 to + 20 ° C, and preferably about 0 ° C. Nitromethane is usually present in excess.

The starting alkali metal salt can be obtained, for example, from the corresponding sulfinic acid of formula VIII by reaction with the corresponding alkali metal hydroxide or (1-6C) alcoholate, such as sodium or potassium methylate or ethylate. The sulfonic acid itself can be obtained by reacting 3,5-dimethylaniline with the corresponding appropriate phenylacetic acid of formula III (or a reactive derivative thereof such as chloride, bromide or anhydride) under conditions analogous to those under which the acylation method is applied, described in (a) above to give the corresponding N-acyl-3,5-dimethylaniline. The acylation is usually carried out with an excess of the acylating agent in the presence of a base such as triethylamine in a suitable solvent or diluent such as t-butylmethyl ether or tetrahydrofuran and at a temperature of, for example, 10 to 40 ° C and preferably at room or near room temperature. N-acyl-3,5-dimethylaniline is then chlorosulfonated by reaction with chlorosulfonic acid to give /

4-N-acylamine-2,6-dimethylphenyl / sulfonyl chloride, the latter being reduced, for example, by suitable sulfite (such as sodium sulfite) in the presence of a suitable buffer (such as sodium hydrogen carbonate) at a temperature of, for example, 60 to 90 ° C. to give (4-N-acylamine-2,6-dimethylphenyl) sulfinic acid.

Alternatively, sulfonyl chloride may also be prepared, for example, from the corresponding 4-N-acyl amine-2,6-dimethyl phenylisothiocyanate by reaction with chlorine in water under conditions analogous to those described in (2). The isothiocyanate itself can be obtained, for example, by reaction of the corresponding 3,5-dimethyl-N-acylaniline with thiocyanogen (obtained from lead (II) thiocyanate and bromine in methyl acetate) or copper (II) thiocyanate in methyl or ethyl acetate.

Then, when a pharmaceutically acceptable salt is required, a compound of formula I may be reacted with a suitable base having a pharmaceutically acceptable cation.

According to another aspect of the invention, it provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The compositions of the invention may be in a variety of formulations for administration. Thus, they may be in a form suitable for oral administration (eg tablets, sugar-coated tablets, hard or soft capsules, liquid or oily suspensions, emulsions, soluble powders or granules, syrups or tinctures), for external use / e.g. creams, ointments, gels or aqueous or liquid solutions or suspensions) or in a form suitable for parenteral administration (for example, sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or vascular dosing) or as suppositories for rectal administration.

The compositions of the present invention can be prepared by conventional procedures using conventional pharmaceutical additives well known to those skilled in the art. Thus, compositions for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservatives, and may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, e.g. calcium carbonate, calcium phosphate or kaolin. Formulations for oral use may also be in the form of soft gelatin capsules in which the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin or olive oil.

Suitable, pharmaceutically acceptable additives for use in tablet formulations include, for example, an inert diluent such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and diluting agents such as corn starch or alginic acid; binders such as gelatin or starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl hydroxybenzoate and antioxidants such as ascorbic acid. The tablets may be uncoated or coated, or to modify their disintegration and subsequent uptake of the active ingredient in the gastrointestinal tract, or to improve their resistance and / or appearance, using conventional coating agents in each case and methodologies that are well known to those skilled in the art.

Aqueous suspensions generally contain the active ingredient as a fine powder together with one or more suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and gumacia; dispersing or moisturizing agents such as lecithin or condensation products of alkylene oxide with fatty acids (eg polyoxyethylene stearate) or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecoethyleneoxyethanol, or esthenic acid, or particle fatty acids and hexitol as mono-oleate of polyoxyethylene sorbitol or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, e.g. p polyethylene sorbitan monooleate. Aqueous suspensions typically contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate), antioxidants (such as ascorbic acid), coloring agents, flavoring agents and / or sweetening agents (such as sucrose, saccharin or asparagine).

Oily suspensions may be made by suspending the active ingredient in vegetable oil (such as peanut, olive, sesame or coconut oil) or in mineral oil (such as liquid paraffin). Oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweeteners such as those mentioned above may be added, as well as flavoring spices, to produce a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water typically contain the active ingredient together with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified above. Additional additives such as sweeteners, spices and colorants may also be present.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin or a mixture thereof. Suitable emulsifying agents may be, for example, natural resins such as gumacation or tragacanth, natural phosphatides such as soybean, lecithin, or esters or incomplete esters derived from fatty acids and hexitol anhydrides (eg sorbitan monooleate), and condensation products from said partial esters, such as ethylene esters, such as esters polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners, spices and preservatives.

Syrups and tinctures may be prepared with sweetening agents such as glycerol, propylene glycol, sorbitol, asparagine or sucrose and may also contain a stabilizer, preservative, spice and / or colorant.

The pharmaceutical compositions may also be in the form of sterile injectable aqueous or oleaginous suspensions, which may be performed according to known methods using one or more of the respective dispersing or wetting agents and suspending agents mentioned above. A sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredient with a suitable, non-irritating carrier, which is a solid at ordinary temperatures but becomes liquid at rectal temperature and therefore melts after being placed in the rectum, thereby releasing the drug . Suitable carriers include, for example, coconut oil and polyethylene glycols.

Formulations for external use, such as creams, ointments, gels, and liquid or oily solutions, can generally be prepared by mixing the active ingredient with a conventional, externally acceptable carrier or diluent using conventional well-known techniques. Formulations for external use intended for the eye are typically in the form of an ointment, gel or sterile solution with a buffer system of the solution with an acceptable eye pH, for example 7.0 - 7.6.

The amount of active ingredient mixed with one or more carriers / additives to form a single dosage will vary depending on the organism being treated and the mode of administration. For example, a formulation for oral administration in humans typically contains from 0.5 mg to 1 g of active agent, combined with an appropriate and appropriate amount of carrier and additives, which can range from about 5 to about 98% by weight. of the total composition. The unit dosage usually contains about 1 mg to about 500 mg of active ingredient.

As indicated, the compounds of the invention retain the enzymatic aldose reductase and are therefore important, for example, for the treatment of those diseases or conditions that are caused by excess amounts of products such as sorbitol formed in the body as a result of processes catalyzed by the enzymatic aldose reductase.

The ability to retain the enzyme aldose reductase in vivo can be demonstrated by the following standard laboratory tests.

Rats became infected with diabetes (evidence of acute glycosuria) by administering streptozotocin. The animals are then given daily for 1, 2 or 5 days for the compound to be tested. Animals were sacrificed 2 - 6 h after the last dose, after which the lens and / or sciatic nerves were removed. Following a standard treatment procedure, residual levels of sorbitol in each tissue were determined by gas-liquid chromatography after conversion to polytrimethylsilyl derivatives. The retention of aldose reductase in vivo can be assessed by comparing the residual levels of sorbitol in the tissues of the treated diabetic rat group with that of the untreated diabetic rat group and the untreated healthy rat group.

In another embodiment of the said test, diabetic rats are given a daily fixed dose of compound for 5 days and then sacrificed 6 h after the last dose, whereby sorbitol reduction in the sciatic nerve is evaluated compared with that in control animals. .

The retention property of the enzyme aldose reductase can also be demonstrated in laboratory conditions. Thus, by a standard procedure, partially purified aldose reductase is isolated in a known manner from bovine lenses. Then, the rate of retention of the ability of this enzyme in vitro to catalyze the reduction of aldoses into alcohols containing several hydrogen atoms which may be substituted and, in particular, to bring glucose to sorbitol as a result of the test compound, using standard spectrophotometric techniques.

In general, most compounds of the present invention show a significant decrease in sorbitol levels in the sciatic nerve at a dose of 5 mg / kg or less in one of the in vivo assays described, together with 1C _JO in the order of 10 ⁸ M to 10 ' M in the described experiments in vitro. By way of illustration, the compound described in Example 1 resulted in an 83% reduction of sorbitol levels in the sciatic nerve after oral administration over 5 days at doses of 3 mg / kg and showed an IC of 11.8 x 10 * M.

A compound of Formula I (or a pharmaceutically acceptable salt thereof) is preferably systemically (usually orally) administered to a warm-blooded animal to produce a therapeutic or prophylactic effect achieved by retaining the enzymatic aldose reductase, for example at a daily dose within 1 up to 40 mg / kg. In humans, the total daily dose to be administered is assumed to be in the range of, for example, 15 to 800 mg per person given, if necessary, in portions. Naturally, the exact amount of compound administered will vary, for example, depending on the age and sex of the patient and the severity and severity of the disease.

A compound of formula I (or a pharmaceutically acceptable salt thereof) may also be administered externally, for example by direct external application to a tissue or organ in which retention of the enzyme is required, for example, in the eye. The exact amount of compound administered necessarily depends on the type of formulation used. For example, when a solution is administered, a concentration of the compound containing up to 0.01% by weight is usually used. Similarly, when an ointment is applied, a compound concentration of up to 2% by weight is usually used. Formulations for the exterior use of a compound of formula I (or a pharmaceutically acceptable salt thereof) may be placed in the eye of an animal, for example a human or a dog, in a conventional manner, such as drops or washes, in cases where treatment and / or prevention of cataracts due to diabetes or retinal disease.

A compound of the present invention may and may conveniently be administered at the same time or close to the time of administration of one or more other agents known to have a beneficial effect in the treatment of diabetes or galactosemia, for example a hypoglycemic agent such as tolbutamide, chlorpropamide or glibenclamide. Any or more of these agents may and suitably be present as an additional active ingredient in a composition according to the present invention.

Although the compounds of the present invention are intended to be used for the treatment or prevention of diseases and conditions in humans and animals caused at least in part by increased levels of tissue sorbitol, they can also be used when the enzyme is required to be retained known as aldose reductase both in laboratory conditions (eg during a research program to identify other therapeutic agents) and in natural conditions (eg in plants where it is necessary to modify notify their development by affecting the metabolism / utilization of aldoses).

The invention is illustrated by the following non-limiting examples which, unless specifically indicated, are conducted under the following conditions:

(I) the solvents were removed by rotary evaporation in vacuo at 40-50 ° C;

(Ii) all operations are performed at room temperature, which is in the range of 18-26 ° C;

(III) Column and high-speed chromatography were performed on silica (Merk Art. 7736), and medium pressure liquid chromatography (MPLC) on silica (Merk Art. 9385), both materials being available from E Merk and Co., Darmstadt, Germany;

(Iv) the characteristics of all end products are determined by microanalysis and NMR spectroscopy;

(V) the yields obtained are given by way of illustration only and are not necessarily the maximum that can be achieved by careful application of the method.

Example 1. Phenylacetyl chloride / 1.16 g,

7.5 mM / was added with stirring to a suspension of calcium carbonate (1.0 g, 10.0 mM) and (4-amine-2,6-dimethylphenylsulfonyl) nitromethane (1.22 g, 5.0 mM) in dry wound tetrahydrofu / THF; 20 ml. The mixture was stirred for 16 h, during which time carbon dioxide was slowly released. Ethanol (1.0 mL) was then added and the mixture was stirred for an additional 1 h to dilute the excess phenylacetyl chloride. Ethyl acetate (100 ml) was then added and the insoluble material was removed by filtration. The filtrate was washed first with water (50 ml) containing 2 M hydrochloric acid (2.0 ml) and then with saturated sodium chloride solution (2 x 40 ml) and then dried (magnesium sulfate). The solvent was evaporated and the residue was recrystallized from ethyl acetate. The resulting solid was washed with ether and dried outdoors to give (2,6-dimethyl-4- (phenylacetamide) phenylsulfonyl) nitromethane as white crystals, m.p. 158-159 ° C and yield 54% after recrystallization from ethanol. The results of microanalysis show: C, 56.7; H, 5.0;

N, 8.0%; C _a H _lg N ₂ O ₅ S requires: C, 56.4; H, 5.0; N, 7.7%.

The starting amino derivative can be prepared as follows.

(1) L-acetyl-3,5-dimethylaniline / obtained as a solid, 138 ° C by acetylation of 3,5-dimethylaniline / was reacted with excess chlorosulfonic acid at 60 ° C according to the analogous procedure described in (3) to give 4-acetamido-2,6-dimethylbenzenesulfonyl chloride as a solid (TLC) (TLC): Rf are.

O, 27 / silica: ethyl acetate / hexane 1: 1 percent by volume // in a yield of about 90%, which is used without drying and without having to determine its characteristics.

(2) Said sulfonyl chloride (10.95 g, 50 mmol) was added to a vigorously stirred solution of sodium bicarbonate (8.4 g, 100 mmol) and anhydrous sodium sulfite (12 g, 95 mmol) in water (50 ml) at temperature 70-80 ° C. The temperature was maintained at 7080 ° C by rhythmic heating. When the addition is complete, the mixture is heated and stirred at 70-80 ° C for another hour. The mixture was then allowed to cool to room temperature for 4 h and acidified with 2 M hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dried in the open to give 4-acetamido-2,6-dimethylbenzenesulfonic acid as a solid and in a yield of about 80%; TLC (thin layer chromatographic analysis): Rf are. 0.02 (silica: ethyl acetate). This acid is converted to the sodium salt by adding to a solution of sodium methylate (1 equivalent) in methanol and evaporating the resulting solution. The sodium salt is used without purification and without having to determine its characteristics.

(3) Nitromethane (6.72 ml, 124 mM) was added to a stirred solution of sodium methylate (3.01 g, 55.8 mM) in N, N-dimethylformamide / DMF; 250 ml /, and cooled in an ice-cold bath to 0 ° C. When the addition is complete, stirring is continued for a further 30 min at 0 ° C. The 4-acetamido-2,6-dimethylbenzenesulfonic acid sodium salt (1, 1.59 g, 56 mmol) was then added, followed directly by iodine (7.2 g, 28.3 mmol). The mixture was stirred for 16 h and allowed to warm to room temperature. A concentrated solution of aqueous sodium sulfite was then added to partially discolour the reaction mixture, which was subsequently poured into water (about 1 l) and acidified with 2 M hydrochloric acid. The aqueous mixture was extracted with ethyl acetate. The combined extracts were washed with water, then with brine and dried (magnesium sulfate). The solvent was removed by evaporation and the residue was purified by flash chromatography over medium (MPLC) on silica, eluting with ethyl acetate-hexane (1:10 percent by volume, gradually increasing to 1: 5), whereby gives (4-acetamido-2,6-dimethylphenylsulfonyl) nitromethane as a solid, m.p. 179-180 ° C (purified by methanol atomization), yield 21%; NMR (d ₆ -DMSQ, 200 MHz): 2.08 (3H, s), 2.54 (6H, s), 6.42 (2H, s), 7.51 / 2H, s), 10.26 (1H, s); microanalysis results: C, 46.2; H, 5.0; N, 9.7%; C ₁₁ H ₁₄ N ₂ O _j S requires: C, 46.15; H, 4.9; N, 9.8%.

(4) (4-acetamido-2,6-dimethylphenylsulfonyl) nitromethane (11.5 g, 40 mM) was added at once to a boiling mixture of concentrated hydrochloric acid (22 ml), water (110 ml) and ethanol (45 ml). /. The mixture was stirred at reflux until a clear solution was formed (for about 20 minutes) and then for another 10 minutes. The hot reaction mixture was then poured into an excess of ice-cold saturated sodium bicarbonate solution. The aqueous mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried (magnesium sulfate) and the solvent removed by evaporation to give (4-amino-2,6-dimethylphenylsulfonyl) nitromethane as a solid, m.p. 132-133 ° C (after recrystallization from ethanol) in 73% yield; NMR (d ^ DMSO, 200 MHz): 2.39 (6H, s), 6.19 (4H, s), 6.35 (2H, s); results from 5 microanalyses: C, 44.5; H, 4.9; N, 11.6%;

C, H _{] 2} N ₂ O ₄ S requires: C, 44.3; H, 4.9; N, 11.5%.

Examples 2-59. Using a procedure similar to that described in Example 1, but using the corresponding acyl chloride, 1θ can yield the following / 4-H-acylamino-

2,6-dimethylphenylsulfonyl / nitromethanes of the present invention.

When- N-acyl group So on- Recrist. To- mayor foam / ° C / solvent (s) was /% /

2 (2,4,6-trimethylphenyl) acetyl 203-204 EtOH 72 3 (2-methylphenyl) acetyl 188-190 Et ₂ O 89 4 (2-fluorophenyl) acetyl 183-184 Et ₂ O 84 5 (2-chlorophenyl) acetyl 188-190 Et ₂ O 80 6 (2-methoxyphenyl) acetyl 140-142 EtOH 28 7 1- (4-chlorophenyl) -1-cyclopropanecarbonyl 150-151 EtOH 68 8 1- (phenyl) -cyclopropanecarbonyl 127-128 EtOO / Hexane 69 9 (4-ethoxyphenyl) acetyl 124-126 EtOO / Hexane 78 10 (R, S) -2- (phenyl) propionyl 175-176 EtOH 71 11 (4-methoxyphenyl) acetyl 182-183 Et ₂ O 99 12 N, N-benzocyclobutanecarbonyl 193-194 EtOH 80 13 (2-bromophenyl) acetyl 188-190 EtOH 79 14 (2-nitrophenyl) acetyl 218-220 Et ₂ O 46 15 2- (4-chlorophenyl) -2-methylpropionyl 197-198 Et ₂ O 75 16 (4-Methoxy-3-methylphenyl) acetyl 143-144 EtOH / Hexane 69 17 (3-fluorophenyl) acetyl 139-141 Et ₂ O 73 18 / R, S / -2-Methoxy-2- (2-fluorophenyl) acetyl 154-155 toluene 35 19 (2-Trifluoromethylphenyl) acetyl 194-196 Et ₂ O 79 20 (3,4-difluorophenyl) acetyl 180-182 Et ₂ O 82 21 (2,6-dichlorophenyl) acetyl 210-212 Et ₂ O 75 22 (4-Trifluoromethylphenyl) acetyl 182-183 Et ₂ O 38 23 (4-chlorophenyl) acetyl 190-191 Et ₂ O 96 24 (3-methyl phenyl) acetyl 168-170 Et ₂ O 63 25 (3-methoxyphenyl) acetyl 140-142 EtOH 28 26 1-Phenylcyclopentanecarbonyl 119-120 EtOH 35 27 1- (4-methoxyphenyl) - 178-179 EtOH 52

cyclopropanecarbonyl

28 (2-naphthyl) acetyl 174-175 Et ₂ O / XekcaH 53 29 N, 5 (-1- (4-chlorophenyl) cyclobutanecarbonyl 147-148 EtOH 36 30 (1-naphthyl) acetyl 213-214 EtOH / Et ₂ O 56 31 (2-methyl-6-nitrophenyl) acetyl 205-207 Is% O 75 32 (4-fluorophenyl) acetyl 161-162 Et ₂ O / XekcaH 90 33 (3,4-dichlorophenyl) acetyl 199-200 EtOH 60 34 35 (2,4-dichlorophenyl) acetyl (R, S) -2- (4-isobutylphenyl) 190-192 EtoAc / Hexane 69 propionyl 116-118 Et ₂ O / XekcaH 23 * 36 (R) -3,3,3-Trifluoro-2-methoxy- 2-phenylpropionyl 106-108 MeOH / H ₂ O 60 37 (S) -3,3,3-Trifluoro-2-methoxy- 2-phenylpropionyl 110-112 MeOH / H ₂ O 66 38 / And, 8 / -2-methoxy- 2- (2-methylphenyl) acetyl 176-177 EtoAc 87 39 (S) -2-Methoxy-2-phenylacetyl 138-140 EtoAc 75 40 (R, S) -1,2,3,4-tetrahydro-1 naphthoyl 120-122 EtoAc 62 41 (R) -2-Methoxy-2-phenylacetyl 140-141 EtoAc / Et ₂ 0 64 42 / R.S/-2- methoxy-2- phenylacetyl 169-170 EtoAc / Hexane 73 43 N, 5 / -2- (2-chlorophenyl) - 2-methoxyacetyl 171-172 Toluene 76 44 (E, 5 / -2- (2-chlorophenyl) - 2-isopropoxyacetyl 180-181 MeOH 10 45 3-indenylcarbonyl 222-224 MeOH 4 46 N, N-1-indenylcarbonyl 181-183 EtOAc 9 47 (R, S) -2- (3-Fluoro-2-methylphenyl) -2-methoxyacetyl 174-176 Et ₂ 0 61 48 (R, S) -2- (2,6-Difluorophenyl) 2-methoxyacetyl 165-167 Et ₂ 0 27 49 (2,6-difluorophenyl) acetyl 195-197 Et 0 67 50 / 1 gizochromanyl / carbonyl 162-163 EtOAc / Hexane 31 51 (R, S) -2-Cyan-2- (phenyl) propionyl 120-121 Toluene 25 52 (R, S) -2-Methoxy-2- (2-methoxyphenyl) acetyl 177-178 Et ₂ 0 87 53 (E, 5) -2- (2,3-difluorophenyl) 2-methoxyacetyl 132-133 Et ₂ O / XekcaH 60 54 (SZ-2-phenylpropionyl) 133-134 Et ₂ O / XekcaH 62 55 (R) -2-Phenylpropionyl 137-138 Et ₂ O / XekcaH 53 56 (R.S/-2-/ 2-methylphenyl) propionyl 142-143 Et ₂ O / Hexane 76 57 /R.S/-2- Phenylbutyryl 140-141 Et ₂ O / XekcaH 49 58 (R, S) -2-Ethoxy-2-phenylacetyl 135-136 Et ₂ O 50 59 (R, S) -2-Ethoxy-2- (2-methylphenyl) acetyl 172-173 Et ₂ O 69

Notes:

1. The following abbreviations are used for the solvents: Et ₂ O - ether; EtOH - ethanol; EtOAc - ethyl acetate; MeOH - methanol; H ₂ O water.

2. Where ether or ether / hexane is indicated as a solvent, it means that it is used to crystallize rather than recrystallize the initially isolated reaction product.

3. * The reaction product is first purified by flash chromatography on silica using dichloromethane as the elution agent.

The starting acyl chlorides may be prepared by conventional methods from the corresponding acids, which are well known and for the most part commercially available. The acids to be used in Examples 38, 43, 44, 47, 48, 52, 53, 58 and 59 are prepared according to the general procedure described in (4), which involves reacting the corresponding benzaldehyde with tetrachloromethane, potassium hydroxide and excess methanol / excl. of Example 44, where 2-propanol is used and Examples 58 and 59, where ethanol is used at a temperature of about 0 to 5 ° C. The acid used in Example 40 was prepared according to the procedure described in (5). The acid used in Example 46 was prepared according to the procedure described in (6). The acid used in Example 50 was prepared according to the procedure described in (7) and the acid used in Example 51 was prepared according to the procedure described in (8).

The preparation of acyl chlorides is illustrated by the preparation of N, S (2-methoxy-2 (phenyl) acetyl chloride as follows.

Oxalyl chloride (2.2 ml, 25 mM) was added to a stirred solution of (R, S) -2-Methoxy-2- (phenyl) acetic acid (3.32 g, 20 mM) in dichloromethane (10 ml). Dry Ν, dimethylformamide (1 drop) was added to catalyze the reaction and the mixture was stirred for 16 h. The solvent was removed by evaporation, leaving (RS) -2-methoxy-2- (phenyl) acetyl chloride as a pale yellow oil that is used without further purification.

Example 60. 3-Chloroperbenzoic acid (55-60%, 1.0 g, 2.9 mM) was added portionwise to a solution of (2,6-dimethyl-4- (2- (2-methylphenyl) acetamide / phenylthio). nitromethane (A) (0.5 g, 1.45 mmol) in chloroform (25 ml) at ambient temperature. The mixture was refluxed for 2 h, then allowed to cool. The sediment from

3-Chlorobenzoic acid was removed by filtration. The resulting filtrate was washed with aqueous sodium metabisulphite solution (2 x 50 ml). The organic phase was dried (magnesium sulfate) and the solvent was removed by evaporation. The resulting cream-colored solid was purified by chromatography on silica and eluted with ethyl acetate / hexane (0-20% by volume) to give (2,6-dimethyl-4- (2-) 2-methylphenyl / acetamide / phenylsulfonyl / nitromethane as a cream-colored solid, m.p. 188190 ° C, m.p. 196-199 ° C after recrystallization from ether (55% yield); NMR (200 MHz, d ₆ -DMSO): 2.29 (s, 3H), 2.55 (s, 6H), 3.31 (s, 2H), 6.44 (s, 2H), 7.1 -7.5 (w, 4H), 7.52 (s, 2H), 10.5 (s, 1H).

The starting phenylthio derivative (A) can be prepared as follows.

(I) Sodium borohydride (2.5 g, 66 mM) was added portionwise to an ice-cold water suspension of 2,6-dimethyl-4- (2- (2-methylphenyl) acetamide / phenylthiocyanate) (B) (5). 0 g, 16 mM (in ethanol (100 ml) and dimethoxyethane (100 ml). After 2 h, water (200 ml) was added to the clear yellow solution. The mixture was acidified to pH 4 with 2 M hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, then with saturated sodium chloride solution and dried (magnesium sulfate). The solvent was removed by evaporation to yield 2,6-dimethyl-4- (2- (2-methylphenyl) acetamide / benzentiol as a creamy solid (4.89 g), which was used without to determine its characteristics.

(II) Said thiol (4.89 g, 17.16 mM) was added to a stirred solution of sodium hydroxide (1.4 g, 35 mM) in water (50 ml) under oxygen conditions. After 10 min, nitromethane (0.93 ml, 17.2 mmol) was added dropwise. The mixture was cooled in an ice bath and a solution of potassium ferricyanide (5.7 g, 17.3 mM) in water (30 ml) was added portionwise. The mixture was stirred at room temperature for 1 hour. Another portion of nitromethane (0.31 ml, 5.7 mM) was added, followed by 10 min of potassium ferricyanide solution (1.9 g, 5.7 mM) in water (20 ml). After 30 min, the aqueous mixture was extracted with ethyl acetate. The combined extracts were washed with water (2 x 50 ml), dried (magnesium sulfate) and the solvent was evaporated. The resulting solid was triturated with ethyl acetate and the solid removed. The filtrate was evaporated, yielding a 62% yield of (2,6dimethyl-4- (2- (2-methylphenyl) acetamide / phenylthio) nitromethane (A) as a light brown solid: NMR / CDCl ₃ , 200 MHz /:

2.28 (s, 3H), 2.4 (s, 6H), 3.65 (s, 2H), 5.6 (s, 2H),

7.1-7.22 (w, 4H), 7.42 (s, 2H), 10.14 (s, 1H).

The starting thiocyanate (B) can be prepared as follows.

(III) Copper thiocyanate (28 g, 155.6 mM) was added to a stirred solution of 3,5-dimethylaniline (7.6 ml, 62.2 mM) in ethyl acetate (150 ml). The mixture was then heated at 60 ° C for 2.5 h, cooled to room temperature, and the solid was removed by filtration through a layer of infuser soil. The residue was washed thoroughly with ethyl acetate. The purple filtrate was washed with 5% w / v. aqueous sodium bicarbonate. The light yellow organic layer was separated, washed successively with water and saturated sodium chloride solution and dried (magnesium sulfate). The solvent was removed by evaporation and the resulting solid was triturated in ether to give 65% yield of 4-amine-2,6-dimethylphenylthiocyanate as a cream-colored solid: NMR: 2.37 / s. 6H (6.43 (s, 2H)).

(Iv) 2- (2-methylphenyl) acetyl chloride /

9.9 g, 58.8 mM / was added to a stirred suspension of calcium carbonate (7.87 g, 78.7 mM) and

4-amine-2,6-dimethylphenylthiocyanate (7 g, 39.3 mm) in dry tetrahydrofuran (150 ml). The mixture was stirred for 1 h. Water (1000 ml) was then added. The mixture was acidified to pH 4 with 2 M hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, then with saturated sodium chloride solution and dried (magnesium sulfate). The solvent was removed by evaporation. The resulting light green solid was triturated with ether to give 83% yield of 2,6-dimethyl-4- (2- (2-methylphenyl) acetamide / phenylthiocyanate (B) as a cream-colored solid. ; NMR (CDCl ₃ , 200 MHz): 2.47 (s, 3H, 2.49 (s, 6H), 3.69 (s, 2H), 7.14-7.17 (w, 4H), 7. 55 (s, 2H), 10.27 (s, 1H).

Alternatively, step (I) and step (II) for the preparation of the phenylthio derivative (A) may be carried out together as follows.

Sodium borohydride (0.24 g, 6.3 mM) was added portionwise to a stirred suspension of 2,6-dimethyl-4- (2- (2-methylphenyl) -acetamide) phenylthiocyanate / 0.5 g, 1.6 mM (in ethanol (20 ml)). After 30 min, acetone (0.47 ml, 6.4 mM) was added to remove excess sodium borohydride and the mixture was stirred for 10 min to give a clear yellow solution containing 2,6-dimethyl -4- (2- (2-methylphenyl) acetamide / benzentiol. Nitromethane (0.09 ml, 1.6 mM) was then added and a solution of potassium ferricyanide (0.53 g, 1.6 mM) in water (10 ml) was added after 10 min. The progress of the reaction was monitored by standard TLC analysis. After 1 h the unreacted thiol remained and therefore nitromethane (0.45 ml, 0.8 mM) and potassium ferricyanide solution (0.27 g, 0.8 mM) in water (5 ml) were added. After about another 1 h, TLC analysis no longer showed thiol. Water (500 ml) was then added. The reaction mixture was acidified to pH 4 with 2 M hydrochloric acid and extracted with ethyl acetate. The extracts were dried (magnesium sulfate) and the solvent was evaporated. The sticky orange-colored solid is sprayed with ether. The orange filtrate was separated and the solid residue was removed. The filtrate was evaporated, yielding a 20% yield of (2,6-dimethyl-4- (2- (2-methylphenyl) acetamide / phenylthio) nitromethane as an orange-brown solid, m.p. 152 ° C (decomposition), which can be used without purification.

Example 61 Nitromethane (5.4 ml, 98 mM) was added to a stirred solution of sodium methylate (2.7 g, 49 mM) in N, N-dimethylformamide (DMF, 250 ml), cooled to about 0 ° C. When feeding is complete, stirring is continued for a further 30 minutes at about 0 ° C. 4- (4- (2-Trifluoromethylphenyl) acetamide) -2,6-dimethylbenzenesulfonic acid sodium salt (16.9 g, 43 mM) (more than 50% concentration according to NMR analysis) was then added, such as sodium salt. iodine (6.35 g, 49 mM) was added immediately thereafter. The mixture was stirred for 16 h and allowed to warm to room temperature. A concentrated solution of aqueous sodium sulfite was then added to partially discolour the reaction mixture, which was then poured into water (about 1 liter). The aqueous mixture was acidified with 2 M hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, then with saturated sodium chloride solution and dried (magnesium sulfate). The solvent was removed by evaporation and the residue was purified by flash chromatography on 60 N silica eluting with ethyl acetate-hexane (1: 10% by volume, gradually increasing to 1: 5% by volume), whereby the solvent was removed. obtains a 10% yield of (4- (2- (2-trifluoromethylphenyl) acetamide) -2,6-dimethylphenylsulfonyl) nitromethane as a solid, m.p. 203204 ° C (after crystallization from ethyl acetate (hexane); NMR (d ₆ -DMSO, 200 MHz): 2.55 (6H, s), 3.8 (2H, s), 6.45 (2H, s), 7.55 (4H, w),

7.7 (2H, d), 10.56 (1H, s); microanalysis results: C, 50.3; H, 4.0; N, 6.4%; C 22 H 27 N 2 O 5 SF 2 requires: C, 50.2; H, 3.98; N, 6.51%.

The starting sulfinic acid can be prepared as follows.

(I) 4- (2- (2-Trifluoromethylphenyl) acetyl-3,5-dimethylaniline), obtained as a solid, m.p. 168 ° C when reacting

2- (2-Trifluoromethylphenyl) acetyl chloride c

3,5-dimethylaniline in tetrahydrofuran solution in the presence of calcium carbonate is reacted with an excess of chlorosulfonic acid at 60 ° C according to a similar procedure to that described in (3), yielding a 47% yield of 4- (2- (2trifluoromethylphenyl) acetamide) -2,6-dimethylbenzenesulfonyl chloride as a solid, which is used without purification.

(II) Said sulfonyl chloride (17.4 g, 43 mM) was added portionwise to a vigorously stirred solution of sodium bicarbonate (7.9 g, 46 mM) and anhydrous sodium sulfite (11.5 g, 92 mm) in water / 92 ml / at a temperature of 70-80 ° C. By rhythmic heating, the temperature is maintained in the range of 70 to 80 ° C. When the feeding is complete, the mixture is heated and stirred at 70-80 ° C for another 1 h. The mixture is then allowed to cool to room temperature for 4 h and acidified with 2 M hydrochloric acid. The precipitated solid was collected by filtration, washed with water, dried outdoors to give crude 4- (2- (2-trifluoromethylphenyl) acetamide) -2,6-dimethylbenzenesulfonic acid as a low-point solid melt mixed with sodium sulfate and the corresponding sulfonic acid. This acid is converted to the sodium salt by the addition of a solution of sodium methylate in methanol to pH 9 and evaporation of the resulting solution. The sodium salt is used without purification and without determining its characteristics.

Examples 62-74. Using a procedure similar to that described in Example 1, but using the starting material for the corresponding acyl chloride instead of phenylacetyl chloride, the following (4N-acylamine-2,6-dimethylphenylsulfonyl) nitromethane of the invention can be obtained:

When- N-acyl group So on- Recrist. To- mayor foam / ° C / dissolve- was tel / s / /% /

62 / + / - 2-methoxy- 2- (2-methyl phenyl) acetyl 152-153 EtOAc noticed. / a / 84 63 N, 8 / -2-ethoxy-2- / 2-fluoro- phenyl / acetyl 132-133 Et ₂ O 61 64 2- (2,3-dimethylphenyl) acetyl 210-211 Et ₂ O 27 65 2- (2,6-dimethylphenyl) acetyl 213-215 Et ₂ O 45 66 (R, 8 / -2- (2,6-difluorophenyl) 82-84 EtOAc / Hexane 20 propionyl 67 / - / - 2-methoxy- 163-164 EtOAc 79 2- (2-methylphenyl) acetyl noticed. / B / 68 2- (4-methylphenyl) acetyl 163-164 Et Ο 85 69 2- (2-fluorophenyl) propionyl 111-113 EtOAc / Hexane 15 70 2- (2,4-dimethylphenyl) acetyl 173-174 EtOAc / Hexane 78 71 / - / - 1,2,3,4-tetrahydro- 180-181 EtOAc 60 1-naphthoyl noticed. / s / 72 / + / - 1,2,3,4-tetrahydro- 178-180 EtOAc 50 1-naphthoyl noticed. / d / 73 2-methoxy-2- [2-methoxy- 138-139 Et ₂ O 87 phenyl / acetyl noticed. / e / 74 / + / - 2-methoxy-2- / 2-methoxy- 139-141 Et ₂ O 86 phenyl / acetyl noticed. / f /

Notes: 35/1 / The following angles of rotation of the polarization plane are obtained for the individual enantiomers obtained above the sodium ^D line at a temperature of approximately 20 ^° C / c = 1 in ethanol or ethyl acetate as 40 solvent:

Note / a / " Solvent 45 / a / + 71 ° EtOAc / B / -69 ° EtOAc / s / -42 ° EtOAc / d / + 40 ° EtOAc / e / -80 ° EtOH 50 / g / + 77 ° EtOH

(2) The starting acyl chlorides can be obtained from the corresponding carboxylic acids by conventional methods, such as the one described above for /

R.S (2-methoxy-2- (phenyl) acetyl chloride. The starting carboxylic acids are generally already known or can be prepared by conventional methods well known to those skilled in the art.

For example, 2-ethoxy-2- (2-fluorophenyl) acetic acid can be prepared as follows.

A solution of potassium hydroxide (22.4 g, 42.8 mM) in ethanol (88 ml) was added over a 3 hour period to a stirred mixture of 2fluorobenzaldehyde (10.0 g, 80.5 mM) and tetrachloroethane (24.3 g, 6.0 mm (in ethanol / 40 mL) at 0 ° C. The mixture was then allowed to reach room temperature and stirred overnight. Water (100 ml) was added and a saturated sodium chloride solution (30 ml) was added in a 50% volume ratio. The mixture was extracted with ether and the extracts were removed. The aqueous phase was warmed to remove traces of ether, acidified to pH 3 with 2 M hydrochloric acid and then extracted with ethyl acetate (2 x 100 ml). The extracts were combined, washed with saturated sodium chloride solution, dried (magnesium sulfate) and the solvent evaporated to give 2-ethoxy-2- (2-fluorophenyl) acetic acid as a light brown oil to be used. without further purification to obtain the corresponding acid chloride.

(3) The individual enantiomers of (R, S) 2-methoxy-2- (2-methoxyphenyl) acetic acid can be obtained by the following separation procedure.

(l, 8 / -2-methoxy-2- (2-methoxyphenyl) acetic acid (20.75 g, 105.9 mM) was dissolved in hot ethanol (53 ml) and quickly added to a vigorously stirred hot solution of /. 15.2 H (- / +) - ephedrine (17.5 g, 105.9 mmol) in ethanol (50 ml). The mixture was allowed to cool to room temperature. The resulting white solid was collected by filtration and recrystallized from ethanol to give the crystalline ephedrine salt (15.65 g). This salt was dissolved in water (150 ml). The solution was acidified by adding 1 equivalent of M hydrochloric acid (43 ml) and then extracted with ethyl acetate (2 x 100 ml). The extracts were washed with water, then with saturated sodium chloride solution, dried (magnesium sulfate) and the solvent evaporated to give (+) -2-methoxy-2- (2-methoxyphenyl) acetic acid. slowly crystallizing oil to give a solid (8.0 g), ²¹ ( ₀ = + 151.8 ° (s - 1, EtOH); optical purity 97,6% e.e. (NMR analysis using a NMR switch reagent / R / - / - / - TFAE).

Using the same procedure but adding (R, S) - (S) - ephedrine to (R, S) -2-Methoxy-2- (2-methoxyphenyl) acetic acid gives (S) -2-methoxy-2- 2-methoxyphenyl / acetic acid as a white crystalline solid (total yield 36.5%), ^{2 |} ( _D - -158.9 ° (s - 1, EtOH); optical purity

99.5% ee (NMR analysis using / R / - / - / - TFAE).

(4) The individual (R) and (S) enantiomers of (R, 8) -1,2,3,4-tetrahydro-1-naphthoic acid can be prepared using the same substantive procedure described in (9) /.

(5) The individual (R) and (S) enantiomers of (5,5) -2-methoxy-2- (2-methylphenyl) acetic acid can be prepared according to a separation procedure analogous to that described in (3), and have the following properties:

/ + / - type: m.p. 69-70 ° C; ²² (d _at + 145 ° (c, 1, ethyl acetate); optical purity 99,5% e.e. (NMR analysis using (R) - / - (TFAE);

/ - / - type: m.p. 66-68 ° C; ²² / / ₀ -139 ° / a - 1 EtOAc /; optical purity 98.3% e.e. (NMR analysis using / R / - / - / - TFAE).

Example 75 A solution of (2,6-dimethyl-4/2-methoxy-2- (2-methoxyphenyl) -acetamide / phenylsulfonyl / nitromethane (2 mM) in methanol (50 ml) was treated with sodium methylate solution / 2 , 05 mM / in methanol (30 ml), cooled to 5 ° C. The mixture was stirred for 10 min and then the solvent was removed by evaporation to give (2,6-dimethyl-4- (2-methoxy-2- (2-methoxyphenyl) acetamide) phenylsulfonyl) nitromethane sodium salt. as a molten solid in a significant amount.

EXAMPLE 76 Representative pharmaceutical dosages containing a compound of general formula I as described in any of the following examples (or a pharmaceutically acceptable salt thereof) for therapeutic or prophylactic use in humans are illustrated below:

/ a / Tablet I mg / tablet

Compound 100

Lactose Ph.Eur. 182.75

Croscarmellose sodium 12,0

Corn starch paste / 5% w / v / 2.25

Magnesium stearate 3.0 / b / Tablet II mg / tablet

Compound 50

Lactose Ph.Eur. 223,75 Croscarmellose sodium 6.0 Corn starch Polyvinylpyrrolidone 15.0 5 / 5% w / v / 2.25 Magnesium stearate 3.0 / in / Tablet III mg / tablet 10 Compound 1.0 Lactose Ph.Eur. 93,25 Croscarmellose sodium Corn starch 4.0 15

/ 5% w / v / 0.75 Magnesium stearate 1.0 / g / Capsule mg / capsule Compound 10 Lactose Ph.Eur. 488,5 Magnesium stearate 1.5

These formulations may be prepared by conventional techniques well known in the art of pharmacy. If necessary, the tablets (a) - (c) for convenience may be enteric coated by conventional means, for example a cellulose triacetate phthalate coating.

Chemical formulas

Chemical formulas / continued /

Claims (11)

Patent claims 1. Phenylacetyl derivative of the compound /4-amino-2,6-dimethylphenylsulfonyl/ nitromethane with formula characterized in that R ⁰ and R* are individually hydrogen, (1-4C)alkyl, (1-4C)alkoxy, cyano or trifluoromethyl, or together represent (2-6)alkylene, or R ¹ together with R ² of the adjacent benzene ring A form methylene, ethylene, oxyethylene, ethyleneoxy, methyleneoxymethylene, vinylene, trimethylene or tetramethylene; in the benzene ring A one, two or three of the available substituents R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are individually selected from hydrogen, halogen, trifluoromethyl, nitro, cyano, (1-4C)alkyl and (1-4C)alkoxy, and the remaining substituents R ² to R ⁶ are hydrogen; or an appropriate pair of the substituents R ² , R ³ , R ⁴ , R ⁵ and R ⁶ forms (together with the adjacent carbon atoms) another benzene ring, which itself may be optionally substituted with a halogen, (1-4C)alkyl or (1-4C)alkoxy substituent, other of the substituents R ² -R ⁶ are hydrogen, halogen, (1-4C)alkyl or (1-4C)alkoxy, trifluoromethyl, nitro or cyano, and the remaining substituents R ² -R ⁶ are hydrogen; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, characterized in that R® and R* are selected from hydrogen, methoxy, ethoxy, isopropoxy, 5θ cyano or trifluoromethyl, or R® and R' together represent ethylene, 1,1-dimethylethylene, trimethylene, tetramethylene or pentamethylene, or R* together with R ² of the adjacent benzene ring A represents methylene, ethylene, oxyethylene, ethyleneoxy, methyleneoxymethylene, vinylene, trimethylene or tetramethylene; and of the benzene ring A one, two or three of the available substituents R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methyl, ethyl, propyl, isopropyl, isobutyl, methoxy and ethoxy, and the remaining substituents R ² -R ⁶ are hydrogen; or an adjacent pair of the present R ² , R ³ , R ⁴ , R ⁵ and R ⁶ forms (together with the adjacent carbon atoms) another benzene ring which may optionally include a fluoro, chloro, methyl or methoxy substituent, the other of the substituents R ² -R ⁶ being hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, methyl, ethyl, propyl, isopropyl, isobutyl, methoxy and ethoxy, and the remaining R ² R ⁶ being hydrogen. 3. A compound according to claims 1 and 2, characterized in that R® and R ¹ represent one of the following combinations /a/ - /f/: /a/ R° and R ¹ are hydrogen; /b/ R° is hydrogen, and R* is methyl; /c/ R® is hydrogen, and ^R1 is ethyl; /d/ R® is hydrogen or methyl, and ^R1 is cyano; /e/ R® is hydrogen or trifluoromethyl, and R* is methoxy or ethoxy; /f/ R® and R ¹ together form ethylene. 4. A bicyclic or tricyclic amide of formula characterized in that Q is methylene, ethylene, oxyethylene, ethyleneoxy, vinylene or trimethylene and the substituents R ³ -R ⁶ on the benzene ring A have one of the meanings defined in claims 1 or 2, or a pharmaceutically acceptable salt thereof. 5. Compound with formula characterized in that Ra and Rb are independently selected from hydrogen, methyl, ethyl or cyano, or one of Ra and Rb is hydrogen or trifluoromethyl and the other is methoxy, ethoxy or isopropoxy; and the benzene ring B is selected from phenyl, 2-halogenophenyl, 2-(1-4C)alkylphenyl, 2-(14C)alkoxyphenyl, 4-(1-4C)alkoxyphenyl and 2,4,6-tri((1-4C)alkyl)-phenyl; or a pharmaceutically acceptable salt thereof. 6. A compound with the formula __/CH, AcylCH—C V-SO ₂ CH ₂ NOj Pa ⁴ ^cn- characterized in that Acyl is selected from: phenylacetyl, /2,4,6-trimethylphenyl/acetyl, /2-methylphenyl/acetyl, /2-fluorophenyl/acetyl, /2-chlorophenyl/acetyl, /2-methoxyphenyl/acetyl, 1 -/4-chlorophenyl/-1 cyclopropanecarbonyl, 1 -/phenyl/-1 -cyclopropanecarbonyl, /4-ethoxyphenyl/acetyl, /R, S/-2-/phenyl/propionyl, /4-methoxyphenyl/ acetyl, /R, 8/-benzocyclobutanecarbonyl, /2-bromophenyl/acetyl, /2-nitrophenyl/ acetyl, 2- /4-chlorophenyl/-2-methylpropionyl, /4-methoxy-3-methylphenyl/acetyl, /3-fluorophenyl/acetyl, /R, 8/-2-methoxy-2-/2-fluorophenyl/acetyl, /2-trifluoromethylphenyl/ acetyl, /3,4-difluorophenyl/acetyl, /2,6-dichlorophenyl/acetyl, /4-trifluoromethylphenyl/acetyl, /4-chlorophenyl/acetyl, /3-methylphenyl/acetyl, /3-methoxyphenyl/acetyl, 1-phenylcyclopentanecarbonyl, 1-(4-methoxyphenyl)-cyclopropanecarbonyl, (2-naphthyl)-acetyl, (R,5)-1-(4-chlorophenyl)-cyclobutanecarbonyl, (1-naphthyl)-acetyl, (2-methyl- 6-nitrophenyl/acetyl, /4-fluorophenyl/ acetyl, /3,4-dichlorophenyl/acetyl, /2,4-dichlorophenyl/acetyl, /R,8/-2-/4-isobutylphenyl/propionyl, /R/-3,3,3-trifluoro-2-methoxy-2-phenylpropionyl, /8/-3,3,3-trifluoro- 2- methoxy-2-phenylpropionyl, /R, B/-2-methoxy-2-(2-methylphenyl)acetyl, /S/-2-methoxy-2-phenylacetyl, /R, S/-1,2,3,4-tetrahydro1-naphthyl, /I/-2-methoxy-2-phenylacetyl, /R, S/-2-(2chlorophenyl)-2-methoxyacetyl, /R, S/-2-(2chlorophenyl)-2-isopropoxyacetyl, 3-indenylcarbonyl, /R, S/-1-indenylcarbonyl, /R, 8/-2-(3-fluoro-2-methylphenyl)-2-methoxyacetyl, /R, 8/-2-(2,6-difluorophenyl)-2-methoxyacetyl, /2,6-difluorophenyl/acetyl, /1-isochromanyl/carbonyl, /R, 8/-2-cyano-2/phenyl/propionyl, /R, 8/-2-methoxy-2-(2-methoxyphenyl/acetyl, /R, 8/-2-(2,3-difluorophenyl/-2-methoxyacetyl, /SZ-2-phenylpropionyl, /RZ-2-phenylpropionyl, /R, S/2-(2-methylphenyl/propionyl, /R, S/-2phenylbutyryl, /R, 8/-2-ethoxy-2-(phenyl/acetyl and /R, B/-2-ethoxy-2-(2-methylphenyl/acetyl; or a pharmaceutically acceptable salt thereof. 7. A compound of formula IIa, characterized in that Acyl is selected from: / R / -2-methoxy-2-(2-methylphenyl)acetyl, / R / -2-ethoxy-2-(2-fluorophenyl)acetyl, 2-(2,3-dimethylphenyl)acetyl, 2-(2,6-dimethylphenylacetyl, / R / -2-/2,6-difluorophenyl/propionyl, / S / -2-methoxy-2-(2-methylphenyl)acetyl, 2-(4-methylphenyl)acetyl, 2-(2-fluorophenyl)propionyl, 2-(2,4-dimethylphenyl)acetyl, / R / -1,2,3,4-tetrahydro-1-naphthyl, / S / -1,2,3,4-tetrahydro-1 -naphthyl, / R / -2-methoxy-2-(2-methoxyphenyl)acetyl and (S)-2-Methoxy-2-(2-methoxyphenyl)acetyl; or a pharmaceutically acceptable salt thereof. 8. A compound of formula 1, characterized in that it is selected from: /2,6-dimethyl-4- [2- /2,4,6-trimethylphenyl /acetamido] phenylsulfonyl /-nitromethane, /2,6-dimethyl-4- [2- /2-methylphenyl /acetamido] phenylsulfonyl-nitromethane, /8/- /2,6-dimethyl-4 [3,3,3-trifluoro-2-methoxy-2-phenylpropionamido]-phenylsulfonyl /nitromethane; /R, S/ - /2,6-dimethyl-4- [2-methoxy-2- /2-methylphenyl /acetamido] -phenylsulfonyl /nitromethane; /8/- /2,6-dimethyl-4- [2-methoxy-2- /2-methylphenyl /acetamido] -phenylsulfonyl /nitromethane; /R, S/ -/2,6-dimethyl-4- [1,2,3,4-tetrahydro-1-naphthylamino] phenylsulfonyl/nitromethane; /R, S//2,6-dimethyl-4-[2-methoxy-2-/2-methoxyphenyl/acetamido] phenylsulfonyl/nitromethane; /R, 8/-/2,6-dimethyl-4- [2-ethoxy-2-phenylacetamido] phenylsulfonyl/nitromethane; /+/-/2,6dimethyl-4- [2-methoxy-2-/2-methylphenyl/acetamido] phenyl/nitromethane; /-/-/2,6-dimethyl4-[1,2,3,4-tetrahydro-1-naphthylamino]phenylsulfonyl/nitromethane and /-/-/2,6-dimethyl-4[2-methoxy-2-/2-methoxyphenyl/acetamido]phenylsulfonyl/nitromethane; or a pharmaceutically acceptable salt thereof. 9. A pharmaceutically acceptable salt according to any one of claims 1 to 8, characterized in that it is an alkali metal salt, an alkaline earth metal salt, an ammonium or aluminum salt or a salt with an organic base capable of releasing a physiologically acceptable cation. 10. A pharmaceutical composition comprising a compound of formula I, Ia, II or IIa, or a pharmaceutically acceptable salt of a compound as defined in any one of claims 1 to 9, together with a pharmaceutically acceptable diluent or carrier. 11. A process for preparing a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: /a/ /4-amino-2,6-dimethylphenylsulfonyl/nitromethane is acylated by reaction with a carboxylic acid of formula or a reactive derivative thereof; /c/ thioether of formula is oxidized; or (c) an alkali metal salt of 4-14-acylamino-2,6-dimethylbenzenesulfinic acid of the formula reacts with nitromethane and iodine in the presence of an alkali metal (1-6C) alcoholate; wherein R°, R ¹ , the benzene ring A and the substituents therein have any of A and the substituents therein have any of the meanings according to claims 1, 2 or 3; and when a pharmaceutically acceptable salt is required, the compound of formula I is reacted with a corresponding base having a physiologically acceptable cation; and when the compound of formula I contains a chiral center, methods (a), (b) or (c) are carried out with a suitable optically active starting material of formula III, IV or VIII, or a racemic mixture of the compound of formula I is resolved.